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In many cases, cells are capable of feats of chemistry that leave human-designed systems in the dust. The problem is that evolution only drives cells that produce the chemicals they need, only in the quantities they need. We design systems to make the chemicals we want and generally take as much as we can produce. Typically, these two things aren't compatible. But some Harvard researchers have figured out a way of getting them into alignment.

It's easy to transplant biochemical pathways into bacteria, at least once you identify the genes involved. At that point, you can have the bacteria produce drugs or other useful chemicals, such as precursors to plastics. The problem is usually that the bacteria aren't happy about it. Producing chemicals generally requires energy, and it siphons off chemical precursors that the bacteria need for their own purposes.

There are two neat tricks that the authors use to induce the bacteria to be happier about being converted into miniature chemical factories. The first is that they figure out how to make the chemical product we want essential to the cell's survival. The second is that they let evolution integrate the new biochemical pathway into the cell.

The first trick relies on the fact that we've identified a huge number of proteins that bind to DNA and activate genes only when a specific chemical is present. Provided you can find a protein that does so in response to the chemical end-product you're looking for, you're set. You simply put the DNA sequence that it binds upstream of an essential gene—one for drug resistance, for example—and the only bacteria that should be able to grow in the presence of the drug are the ones that are making your chemical.

This sounds great on paper, but it's had problems in the real world. Evolution will favor any mutations that activate the drug resistance regardless of whether your protein is present. So the authors used a gene that, at the same time it provides resistance to a drug, leaves the bacteria susceptible to being killed by a different chemical. You just have to alternate between selecting for drug resistance and then adding the lethal chemical. This purges any "cheaters" that have survived without making your chemical of choice.

That handles convincing the bacteria that they want to make your chemical, but how do you make it easier for them to do so?

In this case, the authors used their knowledge of biochemistry. If you understand the pathway, you know the chemical raw materials it siphons off from other processes in the cell along with where those chemicals come from. You could then start tweaking other genes in order to adjust the balance of chemicals to give you more raw materials, in the hope that this will produce more end products.

The problem is that the raw materials are often used by essential processes in the cell, and messing around with them could have unintended consequences. The authors simply subjected all the genes involved in raw material production to lots of random mutations and let evolution sort out the useful variations. Conveniently, the normal process of random mutation was happening at the same time, so many of the mutations that ended up in the strains that grew out weren't even in the genes that were targeted.

The authors tried this with two different chemical end points. In the first, they focused on a chemical (naringenin, a possible drug precursor) that required the insertion of four genes into E. coli before they could produce it at all. After the mutagenesis, however, the resulting strain produced 36 times more of the chemical than when it started. The second chemical they worked on was glucaric acid, a possible replacement for petroleum products in the production of polymers. Here, they saw a 22-fold increase in production following mutagenesis and selection.

Clearly, the technique works. The problem is that you're not always going to have a protein that binds to your molecule of choice and activates genes. The authors argue that this shouldn't be seen as a big problem. There are actually a lot of these genes out there, since they're generally useful to bacteria. We're also discovering new ones all the time. And, if we can't find one, they point out that we're getting better at engineering these sorts of things.

Oddly, the authors don't suggest something that seems like it should have been obvious: we could evolve something using a variation on the same system they just described. Simply by supplying the chemical to the cells, you can select for proteins that bind them and activate the drug resistance gene. We've also evolved lots of RNA molecules that bind to specific chemicals, and we could potentially use those to control gene expression as well.

This doesn't quite mean that we can get bacteria to produce anything. But it certainly seems like a very flexible system.